Construction of C（sp³）—S/Se Bonds via Nickel-Catalyzed Cross-Coupling： Access to Cysteine Derivatives

doi:10.19894/j.issn.1000-0518.250104

Chinese Journal of Applied Chemistry ›› 2025, Vol. 42 ›› Issue (8): 1115-1124.DOI: 10.19894/j.issn.1000-0518.250104

• Full Papers • Previous Articles Next Articles

Construction of C（sp³）—S/Se Bonds via Nickel-Catalyzed Cross-Coupling： Access to Cysteine Derivatives

Gang-Liang DAI, Li-Juan ZHOU, Peng ZHANG, Xin-Yu LI, Mei-Qiu XIAO, TANG-Shi()

College of Chemistry and Chemical Engineering，Jishou University，Jishou 416000，China

Received:2025-03-12 Accepted:2025-06-20 Published:2025-08-01 Online:2025-08-11
Contact: TANG-Shi
About author:stang@jsu.edu.cn
Supported by:
the National Natural Science Foundation of China(22271118)

1. .pdf(4063KB)

Abstract

Abstract:

A nickel-catalyzed cross-coupling reaction between readily available and structurally stable β-bromo amino acid esters and diphenyl disulfide has been developed， enabling the efficient synthesis of a series of novel cysteine derivatives. Employing the Ni（PPh₃）₄/1，10-phenanthroline catalytic system， the reaction proceeds smoothly under mild conditions， affording the target cysteine derivatives in moderate to good yields （58%~82%）. Furthermore， this transformation utilizes a convenient one-pot procedure， successfully constructing the C（sp³）—S bond in a single step. The methodology has been successfully extended to the efficient formation of C（sp³）—O and C（sp³）—Se bonds， facilitating the modular synthesis of selenocysteine and serine derivatives. Featuring mild reaction conditions， operational simplicity， and excellent substrate compatibility， this strategy provides a new approach for synthesizing cysteine and serine derivatives with potential pharmaceutical value.

Key words: Nickel catalysis, Cross-coupling, C（sp³）—S bond, C（sp3）—O/Se bonds, Cysteine derivatives, Serine derivatives

CLC Number:

O622

Gang-Liang DAI, Li-Juan ZHOU, Peng ZHANG, Xin-Yu LI, Mei-Qiu XIAO, TANG-Shi. Construction of C（sp³）—S/Se Bonds via Nickel-Catalyzed Cross-Coupling： Access to Cysteine Derivatives[J]. Chinese Journal of Applied Chemistry, 2025, 42(8): 1115-1124.

Figures/Tables 9

References 25

[1]	CHEN L X， WANG L J， MA L F， et al. Synergistic antioxidant effects of cysteine derivative and Sm-cluster for food applications［J］. Antioxidants， 2024， 13（8）： 910.
[2]	LI S， FU X K， W C L. Organocatalysis with cysteine derivatives： recoverable and cheap chiral catalyst for direct aldol reactions［J］. Res Chem Intermed， 2012， 38： 195-205.
[3]	SHARMA S， ANJANEYULU YAKKALA P， BEG M A， et al. 5-Arylidene-2，4-thiazolidinediones as cysteine protease inhibitors against leishmania donovani［J］. Chem Eur J， 2023， 8（29）： e202302415.
[4]	JUNIOR J C Q， CARLOS F D R R， MONTANARI A， et al. Apoferritin encapsulation of cysteine protease inhibitors for cathepsin L inhibition in cancer cells［J］. RSC Adv， 2019， 9（63）： 36699-36706.
[5]	MENG Y B， HAN S Y， GU Z P， et al. Cysteine-based biomaterials as drug nanocarriers［J］. Adv Ther， 2019， 3（5）： 1900142.
[6]	DE AZEVEDO M D M， TASIC L， FATTORI J， et al. New formulation of an old drug in hypertension treatment： the sustained release of captopril from cyclodextrin nanoparticles［J］. Int J Nanomed， 2011， 6： 1005-1016.
[7]	MOKRA D， MOKRY J， BAROSOVA R， et al. Advances in the use of N-acetylcysteine in chronic respiratory diseases［J］. Antioxidants， 2023， 12（9）： 1713.
[8]	CHUNG C Z， KRAHN N. The selenocysteine toolbox： a guide to studying the 21st amino acid［J］. Arch Biochem Biophys， 2022， 730： 109421.
[9]	PEI J， PAN X， WEI G. Research progress of glutathione peroxidase family （GPX） in redoxidation［J］. Front Pharmacol， 2023， 14： 1147414.
[10]	REDDY K M， MUGESH G. Modelling the inhibition of selenoproteins by small molecules using cysteine and selenocysteine derivatives［J］. Chem Eur J， 2019， 25（37）： 8875-8883.
[11]	ITO S， INOUE S， YAMAMOTO Y. Synthesis and antitumor activity of cysteinyl-3，4-dihydroxyphenylalonines and related compounds［J］. J Med Chem， 1981， 24（6）： 673-677.
[12]	MAREK W， SYLWIA C， PIOTR M. Efficient S-alkylation of cysteine in the presence of 1，1，3，3-tetramethylguanidine［J］. Tetrahedron Lett， 2010， 51（46）： 5977-5979.
[13]	KOLODIAZHNA A О， SKLIAROV А I， SLASTENNIKOVA A A. Asymmetric synthesis of （S，R）- and （R，R）-methiin stereoisomers［J］. Phosphorus Sulfur， 2020， 195（9）： 713-717.
[14]	ZHU F， MILLER E， ZHANG S Q， et al. Stereoretentive C（sp ³）—S cross-coupling［J］. J Am Chem Soc， 2018， 140（51）： 18140-18150.
[15]	AVENOZA A， BUSTO J H， JIMÉNEZ-OSÉS G. Stereoselective synthesis of orthogonally protected α-methylnorlanthionine［J］. Org Lett， 2006， 8（13）： 2855-2858.
[16]	YANG X H， DAVISON R T， DONG V M. Catalytic hydrothiolation： regio-and enantioselective coupling of thiols and dienes［J］. J Am Chem Soc， 2018， 140（33）： 10443-10446.
[17]	KHAN A， ZHAO H， ZHANG M， et al. Regio-and enantioselective synthesis of sulfone-bearing quaternary carbon stereocenters by Pd-catalyzed allylic substitution［J］. Angew Chem Int Ed， 2020， 59（3）： 1340-1345.
[18]	ZHANG J， WU J， CHANG X， et al. An iron-catalyzed multicomponent reaction of cycloketone oxime esters， alkenes， DABCO·（SO₂）₂ and trimethylsilyl azide［J］. Org Chem Front， 2022， 9（4）： 917-922.
[19]	JIANG M， LI H， YANG H， et al. Room-temperature arylation of thiols： breakthrough with aryl chlorides［J］. Angew Chem Int Ed， 2017， 56（3）： 874-879.
[20]	PIEDRA H F， PLAZA M. Photochemical halogen-bonding assisted generation of vinyl and sulfur-centered radicals： stereoselective catalyst-free C（sp ²）—S bond forming reactions［J］. Chem Sci， 2023， 14（3）： 650-657.
[21]	FLEMING F F， GUDIPATI S， VU V A， et al. Grignard reagents： alkoxide-directed iodine-magnesium exchange at sp ³ centers［J］. Org Lett， 2007， 9（22）： 4507-4509.
[22]	SUNDARAVELU N， SANGEETHA S， SEKAR G. Metal-catalyzed C—S bond formation using sulfur surrogates［J］. Org Biomol Chem， 2021， 19（7）： 1459-1482.
[23]	L′ARGENTIÈRE P C， FÍGOLI N S. Poisoning and regeneration of an Ni/SiO₂ catalyst［J］. J Chem Technol Biotechnol， 1997， 69（2）： 261-265.
[24]	LIU Y， XING S Y， ZHANG J， et al. Construction of diverse C—S/C—Se bonds via nickel catalyzed reductive coupling employing thiosulfonates and a selenosulfonate under mild conditions［J］. Org Chem Front， 2022， 9（5）： 1375-1382.
[25]	OVERMAN L E， MATZINGER D， O′CONNOR E M， et al. Nucleophilic cleavage of the sulfur-sulfur bond by phosphorus nucleophiles. kinetic study of the reduction of aryl disulfides with triphenylphosphine and water［J］. J Am Chem Soc， 1974， 96： 6081-6089.

Entry	Additive	Nickel catalyst	Ligand	Base	Solvent	Temperature/℃	Yield/%
1	PPh₃	Ni（PPh₃）₄（0）	L1	K₂CO₃	CH₃CN	60	78
2	None	Ni（PPh₃）₄（0）	L1	K₂CO₃	CH₃CN	60	26
3	PPh₃	Ni（PPh₃）₂（CO）₂（0）	L1	K₂CO₃	CH₃CN	60	52
4	PPh₃	NiBr₂（dme）	L1	K₂CO₃	CH₃CN	60	trace
5	PPh₃	NiCl₂（dime）	L1	K₂CO₃	CH₃CN	60	trace
6	PPh₃	NiCl₂（PPh₃）₂	L1	K₂CO₃	CH₃CN	60	trace
7	PPh₃	Ni（PPh₃）₄（0）	L2	K₂CO₃	CH₃CN	60	65
8	PPh₃	Ni（PPh₃）₄（0）	L3	K₂CO₃	CH₃CN	60	34
9	PPh₃	Ni（PPh₃）₄（0）	L4	K₂CO₃	CH₃CN	60	56
10	PPh₃	Ni（PPh₃）₄（0）	L5	K₂CO₃	CH₃CN	60	47
11	PPh₃	Ni（PPh₃）₄（0）	L6	K₂CO₃	CH₃CN	60	42
12	PPh₃	Ni（PPh₃）₄（0）	L7	K₂CO₃	CH₃CN	60	73
13	PPh₃	Ni（PPh₃）₄（0）	L1	K₃PO₄	CH₃CN	60	12
14	PPh₃	Ni（PPh₃）₄（0）	L1	Na₂CO₃	CH₃CN	60	48
15	PPh₃	Ni（PPh₃）₄（0）	L1	CH₃ONa	CH₃CN	60	24
16	PPh₃	Ni（PPh₃）₄（0）	L1	Cs₂CO₃	CH₃CN	60	16
17	PPh₃	Ni（PPh₃）₄（0）	L1	K₂CO₃	NMP	60	72
18	PPh₃	Ni（PPh₃）₄（0）	L1	K₂CO₃	DMA	60	53
19	PPh₃	Ni（PPh₃）₄（0）	L1	K₂CO₃	DMSO	60	31
20	PPh₃	Ni（PPh₃）₄（0）	L1	K₂CO₃	1，4-Dioxane	60	56
21	PPh₃	Ni（PPh₃）₄（0）	L1	K₂CO₃	CH₃CN（Extra dry）	25	47
22	PPh₃	Ni（PPh₃）₄（0）	L1	K₂CO₃	CH₃CN	25	16
23	PPh₃	Ni（PPh₃）₄（0）	L1	K₂CO₃	CH₃CN	35	36
24	PPh₃	Ni（PPh₃）₄（0）	L1	K₂CO₃	CH₃CN	50	72
25	PPh₃	Ni（PPh₃）₄（0）	L1	K₂CO₃	CH₃CN	70	54

Entry	Additive	Nickel catalyst	Ligand	Base	Solvent	Temperature/℃	Yield/%
1	PPh₃	Ni（PPh₃）₄（0）	L1	K₂CO₃	CH₃CN	60	78
2	None	Ni（PPh₃）₄（0）	L1	K₂CO₃	CH₃CN	60	26
3	PPh₃	Ni（PPh₃）₂（CO）₂（0）	L1	K₂CO₃	CH₃CN	60	52
4	PPh₃	NiBr₂（dme）	L1	K₂CO₃	CH₃CN	60	trace
5	PPh₃	NiCl₂（dime）	L1	K₂CO₃	CH₃CN	60	trace
6	PPh₃	NiCl₂（PPh₃）₂	L1	K₂CO₃	CH₃CN	60	trace
7	PPh₃	Ni（PPh₃）₄（0）	L2	K₂CO₃	CH₃CN	60	65
8	PPh₃	Ni（PPh₃）₄（0）	L3	K₂CO₃	CH₃CN	60	34
9	PPh₃	Ni（PPh₃）₄（0）	L4	K₂CO₃	CH₃CN	60	56
10	PPh₃	Ni（PPh₃）₄（0）	L5	K₂CO₃	CH₃CN	60	47
11	PPh₃	Ni（PPh₃）₄（0）	L6	K₂CO₃	CH₃CN	60	42
12	PPh₃	Ni（PPh₃）₄（0）	L7	K₂CO₃	CH₃CN	60	73
13	PPh₃	Ni（PPh₃）₄（0）	L1	K₃PO₄	CH₃CN	60	12
14	PPh₃	Ni（PPh₃）₄（0）	L1	Na₂CO₃	CH₃CN	60	48
15	PPh₃	Ni（PPh₃）₄（0）	L1	CH₃ONa	CH₃CN	60	24
16	PPh₃	Ni（PPh₃）₄（0）	L1	Cs₂CO₃	CH₃CN	60	16
17	PPh₃	Ni（PPh₃）₄（0）	L1	K₂CO₃	NMP	60	72
18	PPh₃	Ni（PPh₃）₄（0）	L1	K₂CO₃	DMA	60	53
19	PPh₃	Ni（PPh₃）₄（0）	L1	K₂CO₃	DMSO	60	31
20	PPh₃	Ni（PPh₃）₄（0）	L1	K₂CO₃	1，4-Dioxane	60	56
21	PPh₃	Ni（PPh₃）₄（0）	L1	K₂CO₃	CH₃CN（Extra dry）	25	47
22	PPh₃	Ni（PPh₃）₄（0）	L1	K₂CO₃	CH₃CN	25	16
23	PPh₃	Ni（PPh₃）₄（0）	L1	K₂CO₃	CH₃CN	35	36
24	PPh₃	Ni（PPh₃）₄（0）	L1	K₂CO₃	CH₃CN	50	72
25	PPh₃	Ni（PPh₃）₄（0）	L1	K₂CO₃	CH₃CN	70	54

Construction of C（sp³）—S/Se Bonds via Nickel-Catalyzed Cross-Coupling： Access to Cysteine Derivatives

RichHTML

PDF

Supplement

Knowledge

Abstract

Cite this article

share this article

Figures/Tables 9

References 25

Related Articles 7

Recommended Articles

Metrics

Comments

[1]	Ya-Li FENG, Lie-Jin ZHOU, Zhong-Yan CAO. Transition Metal⁃Catalyzed Cross⁃Coupling Reactions of Alkenyl Fluorides： Advances and Perspectives [J]. Chinese Journal of Applied Chemistry, 2022, 39(5): 749-759.
[2]	LI Yuhan, WU Qiang, KANG Chuanqing, GUO Haiquan, JIN Rizhe, GAO Lianxun. Synthesis of 2,3,3',4'-Biphenyltetracarboxylic Dianhydride [J]. Chinese Journal of Applied Chemistry, 2016, 33(8): 900-904.
[3]	ZHOU Wenjun,DENG Jiaying. Research Progress of Iron-catalyzed Cross-coupling Reactions [J]. Chinese Journal of Applied Chemistry, 2016, 33(3): 245-266.
[4]	FENG Cuilan*, XU Haiyun, LIU Lantao, WANG Jing, LIU Ying. Catalytic Synthesis of Diaryl Ethers with Magnetically Recoverable Fe₃O₄ Nanoparticles Under Solvent-free and Ligand-free Conditions [J]. Chinese Journal of Applied Chemistry, 2014, 31(05): 536-540.
[5]	ZHAO Yan1, DENG Jianhui1, LIU Meiling1, LI Haitao1,2, ZHANG Youyu1. Synthesis and Electrochemical properties of Ferrocene-Terminated Phenylethynythiol compounds [J]. Chinese Journal of Applied Chemistry, 2011, 28(10): 1161-1166.
[6]	HE Ying, CAI Chun*. Polymer-supported Nano-palladium as Catalyst for Suzuki Cross-coupling Reaction in Water [J]. Chinese Journal of Applied Chemistry, 2010, 27(07): 792-796.
[7]	TAO Li-Ming1*, LIU Wen-Qi1, TAN Ni2, ZHOU Yun1. Synthesis of 5-Methyl-2,3-diphenyl-1,5-benzothiazepin-4(5H)-one [J]. Chinese Journal of Applied Chemistry, 2010, 27(04): 494-496.